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Protein-based precision medicine overcomes radiation resistance in preclinical leukemia model

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The results of a research effort led by Fatih Uckun from The Saban Research Institute of Children’s Hospital Los Angeles (CA, USA) indicate that the recently engineered protein CD19L-sTRAIL can effectively and safely overcome radiation resistance in leukemia. Uckun describes the need for methods of overcoming this resistance as one of the “most urgent unmet challenges in cancer therapy.”

Long-term survival rates in patients with B-precursor acute lymphoblastic leukemia (ALL) are <20%. Despite ALL being the most common form of cancer occurring in children and adolescents, radiation resistance of leukemia cells sets back the the success of rigorous therapeutic approaches, which include intensive chemotherapy followed by ’supralethal’ chemotherapy, total-body irradiation and hematopoietic stem cell transplantation.

The preclinical study, published in the open access journal EBioMedicine, used mouse models challenged with human ALL cells to measure survival outcomes following radiation therapy combined with the new protein-based precision medicine. The protein, CD19L-sTRAIL, is genetically engineered from CD19 ligand, a protein that seeks out and binds to leukemia cells, fused to soluble TRAIL, a protein that can amplify the potency of radiation.

Low doses of radiation were demonstrated to be highly effective, with the potency of radiation therapy being augmented by CD19L-sTRAIL. Following failure of irradiation alone in mice, the researchers reported that adding 1–3 doses of CD19L-sTRAIL to radiation regimens improved the radiation potency by 260% and resulted in long-term disease-free survival without obvious side effects. Thus, CD19L-sTRAIL exhibited a destructive effect on radiation-resistant primary leukemia cells from ALL patients.

Uckun commented: “Due to its ability to selectively anchor to the surface of leukemia cells via its CD19L portion, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL, and consistently killed aggressive leukemia cells taken directly from children with ALL – not only in the test tube, but also in mice.”

With this report, the research team have published the first proof-of-principle study to demonstrate that radiation resistance of an aggressive leukemia can be overcome using protein-based precision medicine. Uckun continued: “We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia.”

In future practice, the incorporation of CD19L-sTRAIL into pretransplant total-body irradiation patient regimens for very high-risk ALL could improve survival outcomes in many ALL patients.

Sources: Uckun FM, Myers DE, Ma H, Rose R, Qazi S. Low dose total body irradiation combined with recombinant CD19-Ligand×Soluble TRAIL fusion protein is highly effective against radiation-resistant B-precursor acute lymphoblastic leukemia in mice. EBioMedicine DOI: 10.1016/j.ebiom.2015.02.008 (2015); Elsevier press release

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